Fangchinoline, or FAN (also known as Hanfangchin B), is a bisbenzylisoquinoline alkaloid extracted from the root of the Chinese herb fangji powder. Fangchinoline is naturally present in the root of fangji family plant Stephania tetrandra S. Moore, the root of Cyclea peltata Diels and the root and rootstock of thalictrum dichocarpum sutchuenense. Fangchinoline is a natural calcium antagonist and has remarkable therapeutic effects on many diseases. For example, it has broad-spectrum anti-inflammatory and antibacterial effect, anti-hypertension effect, anti-diabetic effect, anti-hepatic fibrosis effect, and protective effect on brain cells. Recent studies have found that it also has significant anti-tumor effect, such as the inhibiting effect on W-256, Ehrlich's ascites carcinoma, and S-45, has inhibiting effect on KB cells and Hela cells, and exhibits strong inhibiting effect on human transplanted liver cancer 7402 and 7405 cell lines.
It is reported that fangchinoline exhibits inhibition on human colon cancer cell line LoVo. In the experiment, nude mice bearing the tumor are subjected to successive administration for 60 days. The results show that, as compared with the control group, the tumor in the administered group remarkably shrinks and grows slowly, and the microvessel density is significantly lower. In addition, during the administration, the mice do not exhibit adverse reactions. This demonstrates that fangchinoline has tumor inhibiting effect in vivo with minimal side effects (Zhenjun Wang et al., Use of fangchinolin in vascularization inhibiting medicine [P]. CN1511528A. 2004).
Changdong Wang et al. studied the inhibition of fangchinoline on human prostate cancer cell PC3. The results showed that the inhibition of fangchinoline on the PC3 cell is dose and time dependent. The studies on the cell cycle process indicated that the inhibition of fangchinoline on the PC3 cell is related to the increase of cells in G1/S phase. In addition, fangchinoline exhibits in vivo antitumor activity by diminishing the tumor volume and promoting the apoptosis and exhibits inhibition on the transplanted tumor PC3 in nude mice (Changdong Wang, et al. Fangchinoline induced G1/S arrest by modulating expression of p27, PCNA, and cyclin D in human prostate carcinoma cancer PC3 cells and tumor xenograft[1]. Biosci. Biotechnol. Biochem. 2010, 74(3):488-493).
Yalin Tang et al. studied the combination of G-quadruplex DNA with fangchinoline to improve the stability of G-quadruplex, thereby reducing the cell proliferation and promoting apoptosis. The experimental results for in vitro antitumor cell proliferation indicate that G-quadruplex DNA, after its combination with fangchinoline, exhibits good inhibiting effect on human leukemia cell line HL-60, human gastric cancer cell line BGC-823, human liver cancer cell line Bel-7402 and human nasopharyngeal cancer cell line KB (Yalin Tang et al., Novel use of bisbenzylisoquinoline alkaloids [P]. CN 101371839A. 2009).
Up to now, there have been few reports on the structural modification and activity of fangchinoline. Recent years have witnessed studies by Fengpeng Wang et al. on the structural modification of fangchinoline, but reports on the related pharmacodynamics activity data have not yet been seen (Fengpeng Wang et al., Dibenzylisoquinoline alkaloids and its preparing process and medical composition [P]. CN 1293196A. 2001).
The present invention conducts structural modification of fangchinoline at its 7′-position hydroxyl group, determines the antitumor activity thereof and discovers that a portion of the novel compounds exhibit significantly improved antitumor activity.